Abstract 34: Impact of Thrombomodulin and Thrombin-activatable Fibrinolysis Inhibitor on the Anti-coagulant and Pro-fibrinolytic Effects of Rivaroxaban
Bibliographic record
Abstract
Rivaroxaban is a novel oral anticoagulant that directly inhibits factor Xa and has recently been implemented as a favorable alternative to warfarin in anticoagulation therapy. Rivaroxaban effectively reduces the generation of thrombin, which plays a major role in the activation of thrombin activatable fibrinolysis inhibitor (TAFI) to TAFIa. Activated TAFI functions by downregulating fibrinolysis, and this effect is highly dependent on the availability of thrombomodulin (TM), as the thrombin-TM complex activates TAFI with a 1250-fold greater efficiency than thrombin alone. Additionally, a naturally occurring SNP in the gene encoding TAFI gives rise to a Thr325Ile polymorphism that increases the stability and antifibrinolytic potential of TAFIa. Since inhibition of thrombin generation could lead to decreased TAFIa formation, we hypothesized that these parameters could influence the pharmacodynamics and pharmacogenomics of rivaroxaban. To assess this, effects on coagulation and fibrinolysis were measured using an in vitro plasma clot lysis assay. Rivaroxaban and TM were titrated into TAFI-deficient plasma in the presence or absence of 10 nM wild-type or T325I recombinant TAFI. With increasing concentrations of rivaroxaban, clot formation latency was accordingly increased. TM further delayed clot formation, and this effect was equal in the absence or presence of either TAFI variant. Rivaroxaban was also shown to decrease the rate of coagulation, which was decreased further at higher concentrations of TM. The presence of either TAFI variant also seemed to decrease clot formation rate at higher levels of rivaroxaban and TM. At all concentrations of TM, TAFI-dependent resistance to fibrinolysis was attenuated by rivaroxaban. The effect of rivaroxaban was, however, greater for wild-type TAFI than for the T325I variant. In conclusion, rivaroxaban exhibits TAFI-dependent profibrinolytic effects that are influenced by the levels of TM and the by intrinsic stability of TAFIa. TM also affected the dynamics of coagulation. These findings suggest a role for the anatomical location of a procoagulant stimulus and plasma TM-altering disease phenotypes in the pharmacodynamics and a role for the T325I polymorphism in the pharmacogenomics of rivaroxaban.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.008 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".